Project Summary Addiction to alcohol represents a major public health issue exacting tremendous financial and social costs. Despite this, alcohol addiction remains a recalcitrant condition with conventional pharmacotherapies lacking substantial and durable efficacy. Much of the existing research into the neurobiology and treatment of alcohol addiction has focused on limbic reward circuitry, changes in neurotransmission, and intracellular neuronal signaling cascades. However, in recent years there has been a surge in research examining the role of epigenetic factors in the development of pathological alcohol use disorders. Epigenetic control of gene expression plays a critical role in processing neural activity in the adult brain, and there is clear evidence in humans and animal models that link changes in brain chromatin to addiction. In recent years, chromatin-bound metabolic enzymes have emerged as central players in epigenetic regulation, leading to a fundamental shift in models of transcriptional regulation, and implicating epigenetic-metabolic processes in the molecular and behavioral response to alcohol. This NIH Pathway to Independence Award (K99/R00) will significantly facilitate the candidate?s, Dr. Mews, ability to begin his career as an independent scientist, allowing him to study new perspectives of this metabolic-epigenetic gene regulation by alcohol, and to explore epigenetic factors as novel therapeutic targets in alcohol use disorders. In the mentored K-phase of this grant (Specific Aim 1 and Specific Aim 2), the contribution of peripheral alcohol metabolism in the liver to histone acetylation in the brain will be determined in a translationally relevant binge drinking model in rodents. Alcohol-induced histone acetylation will be assayed both locally and globally in the hippocampus, a region intimately linked to alcohol addiction vulnerability, and the direct modulation of gene expression by alcohol-derived acetate that originates in hepatic alcohol metabolism will be tested. Further, viral manipulation of gene expression to manipulate acetyl-CoA metabolism will be used to establish causality and determine whether the metabolic-epigenetic ACSS2 pathway links alcohol-driven histone acetylation to increased consumption and alcohol-related learning. In the independent phase (R00), Specific Aim 3, we will combine these conceptually and technically innovative approaches with translational binge drinking models to investigate the chromatin-based targeting mechanisms that allow ACSS2 to regulate specific gene expression induced by alcohol in the brain. In summary, the research proposed in this Pathway to Independence Award will illuminate the metabolic-epigenetic mechanisms by which alcohol influences neuronal processes as well as alcohol-related learning and drinking behavior; while simultaneously preparing the candidate with an unique set of intellectual and technical skills that will allow him to develop a fully independent research program on alcohol addiction that is capable of integrating a wide range of neuroepigenetic and behavioral approaches in a technically advanced and high impact manner.